Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method

ABSTRACT

The present invention is directed to a cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, in particular a blood sample, comprising a cartridge body having at least one measurement cavity formed therein and having at least one probe element arranged in said at least one measurement cavity for performing a test on said sample liquid; and a cover being attachable on said cartridge body; wherein said cover covers at least partially said at least one measurement cavity and forms a retaining element for retaining said probe element in a predetermined position within said at least one measurement cavity. The invention is directed to a measurement system and a method for measuring viscoelastic characteristics of a sample liquid.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application and claims the benefit ofco-pending U.S. application Ser. No. 16/146,333, filed Sep. 28, 2018,which is a continuation of co-pending U.S. application Ser. No.15/869,782, filed Jan. 12, 2018, which is a continuation application andclaims the benefit of U.S. application Ser. No. 15/357,492, filed Nov.21, 2016, now U.S. Pat. No. 9,915,671, issued on Mar. 13, 2018, which isa continuation application and claims the benefit of U.S. applicationSer. No. 15/066,605, filed Mar. 10, 2016, now U.S. Pat. No. 9,739,789,issued on Aug. 22, 2017, which is a continuation application and claimsthe benefit of U.S. application Ser. No. 13/895,034, filed on May 15,2013, now U.S. Pat. No. 9,285,377, issued on Mar. 15, 2016, which is acontinuation application of and claims the benefit of U.S. applicationSer. No. 12/640,376, filed on Dec. 17, 2009, now U.S. Pat. No. 8,448,499issued on May 28, 2013, which claims priority to and the benefit of U.S.Provisional Application No. 61/140,344 filed on Dec. 23, 2008. Thisapplication is related to the U.S. application Ser. No. 13/895,053 filedon May 15, 2013, now U.S. Pat. No. 9,086,423, issued on Jul. 21, 2015,to the U.S. application Ser. No. 13/895,002, filed on May 15, 2013, nowU.S. Pat. No. 8,857,244 issued on Oct. 14, 2014, and to U.S. applicationSer. No. 13/894,998, filed on May 15, 2013, now U.S. Pat. No. 9,110,084issued on Aug. 18, 2015, which are continuation applications of andclaim the benefit of U.S. application Ser. No. 12/640,376, filed on Dec.17, 2009, now U.S. Pat. No. 8,448,499 issued on May 28, 2013, whichclaims priority to and the benefit of U.S. Provisional Application No.61/140,344 filed on Dec. 23, 2008. The entire contents of each of theabove patents and applications are incorporated herein in their entiretyby reference for all purposes.

FIELD OF THE INVENTION

The present invention relates to a cartridge device for a measuringsystem for measuring viscoelastic characteristics of a sample liquid, inparticular of a blood sample liquid. The present invention also relatesto a corresponding measuring system and method.

It is essential for survival that a wound stops bleeding, i.e. that thebody possesses an adequate mechanism for haemostasis. The process ofblood clotting can be activated in the case of injuries or inflammationsby either extrinsic or intrinsic factors, e.g. tissue factor (TF) orHagemann factor (F XII), respectively. Both activation channels arecontinued in a common branch of the cascade resulting in thrombinformation. The thrombin itself finally initiates the formation of fibrinfibres which represent the protein backbone of blood clots.

The other main constituent of the final blood clot are the thrombocyteswhich are interconnected by the fibrin fibres and undergo a number ofphysiological changes during the process of coagulation. Within limits alack of thrombocytes can be substituted by an increased amount of fibrinor vice versa. This is reflected in the observation that the thrombocytecounts as well as the fibrinogen concentration varies even within ahealthy population.

Various methods have been introduced to assess the potential of blood toform an adequate clot and to determine the blood clots stability. Commonlaboratory tests such as thrombocyte counts or the determination offibrin concentration provide information on whether the tested componentis available in sufficient amount but lack in answering the questionwhether the tested component works properly under physiologicalconditions (e.g. the polymerisation activity of fibrinogen underphysiological conditions can not be assessed by common optical methods).Besides that, most laboratory tests work on blood-plasma and thereforerequire an additional step for preparation and additional time which isunfavourable especially under POC (point of care) conditions.

Another group of tests which overcomes these problems is summarized bythe term “viscoelastic methods”. The common feature of these methods isthat the blood clot firmness (or other parameters dependent thereon) iscontinuously determined, from the formation of the first fibrin fibresuntil the dissolution of the blood clot by fibrinolysis. Blood clotfirmness is a functional parameter, which is important for haemostasisin vivo, as a clot must resist blood pressure and shear stress at thesite of vascular injury. Clot firmness results from multiple interlinkedprocesses: coagulation activation, thrombin formation, fibrin formationand polymerization, platelet activation and fibrin-platelet interactionand can be compromised by fibrinolysis. Thus, by the use of viscoelasticmonitoring all these mechanisms of the coagulation system can beassessed.

A common feature of all these methods used for coagulation diagnosis isthat the blood clot is placed in the space between a cylindrical pin andan axially symmetric cup and the ability of the blood clot to couplethose two bodies is determined.

The first viscoelastometric method was called “thrombelastography”(Hartert H: Blutgerinnungsstudien mit der Thrombelastographie, einemneuen Untersuchungsverfahren. Klin Wochenschrift 26:577-583, 1948). Asillustrated in FIG. 1, in the thromboelastography, the sample as asample liquid 1 is placed in a cup 2 that is periodically rotated to theleft and to the right by about 5°, respectively. A probe pin 3 is freelysuspended by a torsion wire 4. When a clot is formed it starts totransfer the movement of the cup 2 to the probe pin 3 against thereverse momentum of the torsion wire 4. The movement of the probe pin 3as a measure for the clot firmness is continuously recorded and plottedagainst time. For historical reasons the firmness is measured inmillimeters.

The result of a typical measurement of this kind is illustrated in FIG.2. One of the most important parameters is the time between theactivator induced start of the coagulation cascade and the time untilthe first long fibrin fibres have been build up which is indicated bythe firmness signal exceeding a defined value. This parameter will becalled clotting time or just CT in the following. Another importantparameter is the clot formation time (CFT) which gives a measure for thevelocity of the development of a clot. The CFT is defined as the time ittakes for the clot firmness to increase from 2 to 20 mm. The maximumfirmness a clot reaches during a measurement, further on referred to asmaximum clot firmness or just MCF, is also of great diagnosticimportance.

Modifications of the original thromboelastography technique (Hartert etal. (U.S. Pat. No. 3,714,815) have been described by Cavallari et al.(U.S. Pat. No. 4,193,293), by Do et al. (U.S. Pat. No. 4,148,216), byCohen (U.S. Pat. No. 6,537,819). A further modification by Calatzis etal. (U.S. Pat. No. 5,777,215) illustrated in FIG. 3 is known under theterm thromboelastometry.

Contrary to the modifications mentioned above, thromboelastometry isbased on a cup 2 fixed in a cup holder 12 while the probe pin 3 isactively rotated. For this purpose the probe pin 3 is attached to ashaft 6 which is suspended by a ball bearing 7 in a base plate 11 andhas a spring 9 connected to it. An oscillating motion perpendicular tothe drawing plane induced at the opposite end of the spring istransformed into a periodically rotation of the shaft 6 and theconnected cup 2 around a rotation axis 5 by about 5° in each direction.As the sample liquid 1 begins to coagulate the motion amplitude of theshaft 6 which is detected by the deflection of a light beam fromdetecting means 10 and a mirror 9 starts to decrease.

During coagulation the fibrin backbone creates a mechanical elasticlinkage between the surfaces of the blood-containing cup 2 and a probepin 3 plunged therein. A proceeding coagulation process induced byadding one or more activating factor(s) can thus be observed. In thisway, various deficiencies of a patient's haemostatic status can berevealed and can be interpreted for proper medical intervention.

A general advantage of viscoelastometric, e.g. thromboelastometric,techniques compared to other laboratory methods in this field thereforeis that the coagulation process and the change of mechanical propertiesof the sample are monitored as a whole. This means that—in contrary toother laboratory methods mentioned above-thromboelastometry does notonly indicate if all components of the coagulation pathways areavailable sufficient amounts but also if each component works properly.

To obtain detailed information on the correct amount and function of thethrombocytes as well as the fibrinogen and certain factors nowadaysthere is an increasing amount of compounds available which activate orinhibit certain components of the coagulation system. This allowsdetermining at which point of the coagulation system a problem islocated.

For practical reasons theses compounds are usually injected into thedisposable plastic cup which later on is used for the measurement byusing a pipette (either a manual or an automatic one). In the lastpreparation step, after the blood or plasma sample has been added, thewhole amount of sample (blood/plasma and the additional chemicals) ismixed by drawing it into the pipette tip and dispensing it into the cupagain.

The possibility to activate or to inhibit certain components of thecoagulation system is especially useful in conjunction withstate-of-the-art thromboelastometers such as the ROTEM (Pentapharm GmbH,Munich, Germany) which allows conducting four measurements in parallel.This allows detailed information on the current status of thecoagulation-situation of a patient to be achieved and therefore allowsan appropriate therapy within several minutes.

This is of particular importance in case of patients struck by massiveblood loss as it often occurs in context with multiple traumata or majorsurgery. The blood of such patients often is diluted due to infusionswhich are administered to replace the loss in volume. This leads to adecrease of the concentration of thrombocytes as well as coagulationfactors including fibrinogen.

Main advantages of thromboelastometry and thromboelastography are thepossibility to perform several differential tests in parallel in orderto precisely determine which kinds of blood products are the appropriatemedication, the possibility to perform the measurement at or close tothe point of care (POC) and—compared to other methods—the relativelysmall amount of time until valid results are available.

On the other hand the operator has to perform a significant number ofsteps in order to start the measurement (preparation of the reagents,attachment of the probe pin and the cup to the instrument, pipetting andmixing the blood sample and the reagents, adjustment of computersettings, etc.) on which the time spent is considerable, especially inthe case of surgery being performed.

Furthermore this rather complex preparation also increases the risk ofoperating errors. There have been several approaches to simplify theusage of thromboelastometers. The Rotem-System (Pentapharm GmbH, Munich,Germany) e.g. is supplied with an automatic pipette which simplifies thehandling to a large degree and thereby decreases the risk of operatingerrors.

WO 2008093216 describes the approach to provide the adequate amount ofeach of the reagents needed for one specific test in a ready-to-usemixture. In order to prevent the reaction of the reagents prior to themeasurement, they are supplied in a lyophilisate state. This isadditionally advantageous as the reagents can be stored at roomtemperature. Using this approach the preparation is reduced to the stepsof adding the blood sample into the reagent container, mixing of bloodwith the reagent and transferring the mixture to the instrument.

US 2007/0059840 A1 describes a hemostasis analysis device and method.The device includes a container for holding a sample to be tested and abobber configured to be buoyantly suspended on the sample. A magnet issecured to the bobber. The container can be driven in an oscillatingmotion. An external magnetic field is generated adjacent to the bobber.A magnetic field strength detector detects changes in the magnetic fieldas a result of movement of the bobber and magnet responsive to theoscillating motion of the container and clotting of the sample.

Such a new measuring system entails acceptability problems anduncertainties for a user. Moreover, that analysis device does not fit inexisting measuring systems. Therefore new systems have to be completelydesigned.

All these modifications lead to a significant improvement of handling ofmodern thromboelastometers and thromboelastographs, however, nosuccessful approach to develop a widely automated technique has beenmade since Hartert's invention 60 years ago. One of the two main reasonsof that is the fact that the measurement requires two disposable parts(cup and pin) being moved in relation to each other and thus have to bereversibly attached to different parts of the measurement device. E.g.in FIG. 3, the probe pin 3 is attached to the shaft 6 and the cup 2 tothe cup holder 12, respectively. The other main reason is that differenttests are required to get comprehensive information of a currentbleeding status of a patient. These different tests require differentreagents which have to be mixed with the blood sample.

SUMMARY OF THE INVENTION

It is a problem underlying the presented invention to provide acartridge device for a measuring system for measuring viscoelasticcharacteristics of a sample liquid, in particular a blood sample.

Directly connected to this invention is the problem to provide acorresponding measuring system for measuring viscoelasticcharacteristics of a sample liquid, in particular the coagulationcharacteristics of a blood sample liquid.

It is a further problem underlying the invention to provide a method formeasuring viscoelastic characteristics of a sample liquid using saidmeasuring system.

These problems are solved by the subject-matter of the independentclaims. Preferred embodiments are set forth in the dependent claims.

In a first aspect, the present invention provides a cartridge device fora measuring system for measuring viscoelastic characteristics of asample liquid, in particular a blood sample, comprising

a cartridge body having at least one measurement cavity formed thereinand having at least one probe element arranged in said at least onemeasurement cavity for performing a test on said sample liquid; and

a cover being attachable on said cartridge body;

wherein said cover covers at least partially said at least onemeasurement cavity and forms a retaining element for retaining saidprobe element in a predetermined position within said at least onemeasurement cavity.

In a second aspect, the present invention provides a measuring systemfor measuring viscoelastic characteristics of a sample liquid, inparticular a blood sample, comprising: at least one interface element;at least one shaft rotatably supported by the interface element to berotated by drive means; at least one cartridge device fixed to theinterface element for holding the sample liquid, the at least onecartridge device comprising a cartridge body with a cover and at leastone probe element arranged in a measurement cavity formed in saidcartridge body for cooperating with the at least one shaft; at least onedetecting means cooperating with the shaft for measuring viscoelasticcharacteristics of the sample liquid; and

control means to control the measuring system.

In a third aspect, the present invention provides a method for measuringviscoelastic characteristics of a sample liquid by means of saidmeasuring system, comprising the following steps:

a) providing the cartridge device having at least one measurement cavitywith at least one probe element arranged therein;

b) attaching the cartridge device to said interface element, said shaftbeing inserted into said probe element;

c) filling said measurement cavity of said cartridge device with sampleliquid;

d) rotating said shaft in an oscillating motion around said rotationaxis; and

e) measuring viscoelastic characteristics of said sample liquid bydetecting the rotation of said shaft by said detecting means.

In a preferred embodiment the probe element comprises a probe pin tocooperate with the sample liquid and a connector section for aconnection to the measuring system. The connector section is formed e.g.as a bore extending within the probe element and comprises frictionalconnection means which can be e.g. clip means or a thread. An insertionguide facilitates an insertion of a part, in particular a shaft, of ameasuring system. Thereby the shaft can be connected securely to theprobe element.

The at least one measurement cavity can comprise bearing or supportingmeans for the probe element to align or hold the probe element prior toinsertion of the shaft.

After the shaft has been inserted into the connector section, the shaftcan be lifted to position the probe element at a working position.

In an alternative preferred embodiment the probe element is formed as adetachably fixed component part of the cover. An operator only has toattach the cartridge device to the measuring system the shaft beinginserted into the probe element will detach the probe element from thecover and hold it securely in a position ready to carry out ameasurement. Therefore the probe element comprises a fixing section fordetachably fixing the probe element at fixing means of the cover.

After a measurement the cartridge device can be detached from themeasuring system wherein the shaft is removed from the probe element.Then the probe element will seal the measurement cavity against thecover by means of e.g. a flange adapted to form a sealing. The coverretains the probe element within the measurement cavity.

It is preferred that the fixing means of the cover comprises clip meanscooperating with corresponding clip means of the fixing section of theprobe element.

In an alternative embodiment the fixing section of the probe element isintegrally formed with the cover, the fixing means of the covercomprising a perforation.

The cover can be fixed on the cartridge body either by bonding orwelding. In an alternative embodiment the cover is integrally formedwith the cartridge body, e.g. made of a plastic material. It is alsopossible that the cover is made of a material which is different fromthe cartridge body. That can be done for example by two- ormore-component-moulding.

In a further preferred embodiment the cartridge device further comprisesat least one receiving cavity formed therein for receiving the sampleliquid; at least one reagent cavity for holding at least one reagent; aductwork connecting said cavities and the at least one measurementcavity; and at least one pump means connected to the ductwork fortransporting the sample liquid from the at least one receiving cavity tothe at least one measurement cavity by means of the ductwork, whereinthe cover covers and at least partially forms said cavities and saidductwork and forms at least partially the pump means.

In a further embodiment the at least one reagent cavity is integrallyformed with the pump means or/and with the at least one measurementcavity or/and with one or more of the ductworks. The reagent cavity canbe formed as a deep cavity or just a small place where reagent can bedeposited. Thus the sample liquid being pumped through the ductwork andthe pump means into the measurement cavity can be mixed with thereagent.

The pump means comprise at least one valve for a directed flow of thesample liquid in order to direct the pumped liquid into the measurementcavity.

In another embodiment the reagent or an additional reagent can be storedin at least one reagent receptacle which can be opened by externalmeans.

In a further embodiment the at least one reagent receptacle storing areagent is integrated in the cover.

In another embodiment the at least one reagent receptacle comprises abottom part which can be opened by external means to discharge thereagent into the ductwork and/or into one of the cavities. Thereceptacle can be adapted as a blister receptacle, for example.

The at least one reagent can be stored within the cartridge device inpulverized, solid or liquid form.

The cartridge device can be further provided with at least one reagentstored therein.

Filling in sample liquid can be done directly into the measurementcavity if no receiving cavity is provided. To this end the sample liquidcan be injected through the cover via an opening or passage hole in theinterface element or through a ductwork by an operator or by a controlapparatus.

In case of a receiving cavity the sample liquid can be filled into thereceiving cavity and be pumped by the pump means to the measuringcavity.

To fill in sample liquid, operate the pump means, add reagents and/oropen the reagent receptacle the measuring system is equipped with acontrol apparatus. The control apparatus has means to access the pumpmeans through a pump access formed as a passage of the interfaceelement. Further the control apparatus can inject sample liquid throughan inlet opening in the interface element into the receiving cavity. Thecontrol apparatus comprises also operating means to inject or to addreagents into the cartridge device as well as to open reagentreceptacles.

Further features and advantages of the present invention will be evidentfrom a description of embodiments with reference to the figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The figures are showing the following:

FIG. 1 is a schematic drawing of the principle of thromboelastographyaccording to Hartert.

FIG. 2 is an exemplary diagram showing a typical thromboelastometricmeasurement.

FIG. 3 is a schematic drawing of the thromboelastometry.

FIG. 4 is a schematic drawing of a first embodiment of a cartridgedevice according to the invention.

FIG. 5 is a schematic drawing of a variation of the first embodiment ofthe cartridge device according to the invention.

FIG. 6 is a schematic drawing of another variation of the firstembodiment of the cartridge device according to the invention.

FIG. 7a is a schematic drawing of a first embodiment of a probe element.

FIG. 7b is a schematic drawing of the first embodiment of the probeelement of FIG. 7a within a measuring cavity of the first or a secondembodiment of the cartridge device according to the invention beforeuse.

FIG. 7c is a schematic drawing of the first embodiment of the probeelement of FIG. 7a within a measuring cavity of the first or the secondembodiment of the cartridge device according to the invention in use.

FIGS. 8a-c are technical drawings of the preferred probe element of FIG.7 a.

FIG. 9a is a side view of a third embodiment of a cartridge deviceaccording to the invention.

FIG. 9b is a sectional view B-B of the cartridge device of FIG. 9 a.

FIG. 9c is a sectional view C-C of the cartridge device of FIG. 9 a.

FIG. 9d is a sectional view D-D of the cartridge device of FIG. 9 a.

FIG. 10a is a top view of the cartridge device of FIG. 9 a.

FIG. 10b is a sectional view E-E of the cartridge device of FIG. 10 a.

FIG. 11a is a sectional view of a pump means of the cartridge device ofFIG. 9 a.

FIG. 11b is a sectional view of the pump means of FIG. 11a in operatedposition.

FIG. 12 is a schematic top view of the pump means of FIG. 11 a.

FIG. 13a is a side view of an embodiment of a measuring system accordingto the invention.

FIG. 13b is a top view of the measuring system of FIG. 13 a.

FIG. 13c is a sectional view H-H of the measuring system of FIG. 13 b.

FIG. 14 is a sectional view of a reagent receptacle of a thirdembodiment of the cartridge device according to the invention.

FIG. 15 is a schematic drawing of a second embodiment of the probeelement.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

Parts and components having same functions are depicted with samereferences.

Prior to a detailed description of the preferred embodiments the basicfeatures and a basic practical implementation are summoned as follows.All embodiments refer to a cartridge device 50 (see FIG. 13c ) which canbe formed in a first embodiment (see FIGS. 4, 5 and 6), in a secondembodiment (see FIGS. 7b, 7c and 15) or in a third embodiment (see FIGS.9 to 10). The cartridge device 50 contains all parts coming into contactwith a sample liquid 1 to be tested. These can be also reagents thesample liquid has to be mixed with for a measurement. The cartridgedevice 50 is part of a measuring system 40 (see FIG. 13c ) to which thecartridge device 50 is attached before measurement. The measuring system40 also comprises a control apparatus (not shown) which has been adaptedto interact with the cartridge device 50 by electrical and/or mechanicalmeans to control flow of sample liquid 1 (see FIG. 7c ) and measurementsas well as collect data. Furthermore this apparatus contains mechanicaland electronic parts required for measurement, data analysis and userinteraction. The present invention is not only suitable forthromboelastometry, thromboelastography and platelet aggregometry butalso for other blood tests usually performed regarding surgery.

A first embodiment of a cartridge device 50 of the invention will bedescribed with reference to FIGS. 4 and 5. The cartridge device 50 forthe measuring system 40 for measuring medical relevant, e.g.viscoelastic, characteristics like coagulation or platelet function of asample liquid 1, particularly a blood sample, comprises a receivingcavity 16 for receiving the sample liquid 1, pump means 18 for pumpingthe sample liquid, a reagent cavity 19 for storing a reagent 21, ameasurement cavity 20 for measuring the sample liquid 1 and a ductworkconnecting said cavities. The ductwork comprises an inlet duct 13 fromthe receiving cavity 16 to the pump means 18, an intermediate duct fromthe pump means 18 to the reagent cavity 19 and an outlet duct 15 fromthe reagent cavity 19 to the measurement cavity 20. In a variation saidcavities and ducts can be arranged in different ways one of which isshown in FIG. 5, wherein pump means 18 and reagent cavity 19 arechanged.

In this embodiment the receiving cavity 16 consists of a cavity withinthe cartridge device 50. The sample liquid 1 can be applied by means ofa syringe, pipette etc, e.g. through a self sealing cap shown as areceiving cavity cover 33 a in FIG. 10b . By operating the pump means18, e.g. by means of the control apparatus mentioned above, the sampleliquid is transported to the reagent cavity 19, where the reagent 21required for measurement is mixed with the sample liquid 1. Furtherpumping the sample liquid 1 will transfer it into the measurement cavity20 in which the measurement (described below) is carried out.

In an alternative embodiment the reagent cavity 19 is integral formedwith the pump means 18 and/or with the measurement cavity 20 and/or withthe ductwork. The transport of the sample liquid 1 can be controlled bysaid control apparatus.

FIG. 6 shows another variation of the first embodiment. Two arrangementsof FIG. 4 with only one receiving cavity 16 are arranged in parallel,wherein a first inlet duct 13 communicates with a second inlet duct 13′connected to second pump means 18′. A second intermediate duct 14′ leadsto a second reagent cavity 19′ storing a second reagent 21′. A secondoutlet duct 15′ connects the second reagent cavity 19′ to the secondmeasurement cavity 20′. FIG. 6 shows only one possible variation of aplurality of different arrangements easily imagined. The sample liquid 1is shared among the arrangements in parallel. Controlled by the externalcontrol apparatus the shared portions of the sample liquid 1 are mixedwith different reagents 21, 21′ during transport.

It is apparent to a person skilled in the art that in order to achieve amaximum benefit for a user different types of tests can be combined inone cartridge device 50.

In a preferred embodiment the cartridge device 50 comprises fourarrangements of FIG. 4 or 5 having 4 measurement cavities 20, 20′. Thusmeasurements can be done with different reagents on the same liquidsample or with same reagents as well to check plausibility.

Regarding e.g. blood coagulation there are different reagents availablewhich activate or suppress different parts of the coagulation cascade.Pentapharm GmbH (Munich, Germany) for example amongst others providetests for intrinsic and extrinsic activation of a blood sample (INTEM orEXTEM respectively), and also a test for extrinsic activation in whichthe thrombocyte function is suppressed by administration of cytochalasinD (FIBTEM). It is state of the art that it is possible by wisecombination of such tests to be able to determine very precisely atwhich point within the coagulation cascade a problem occurs. This is ofgreat importance in order to determine a proper medication. Bycomparison of the results on an EXTEM test of a pathologic sample tothose of a FIBTEM test of the same sample it is possible to e.g.precisely determine if a coagulation disorder results from lack offibrinogen or a malfunction of platelets. Generally, there are differenttypical medical scenarios in which coagulation disorders are very likelyto occur. For example coagulation disorders occurring during livertransplantation are merely caused by lack of certain coagulation factorsetc., while coagulation disorders during open heart surgery are mostlikely due to the influence of heparin. This means basically thatdifferent medical settings require different coagulation tests.Referring to FIG. 6 it is possible and worthwhile to provide differentcartridge devices 50 for different typical operations. It is alsopossible to combine e.g. an INTEM, an EXTEM and a FIBTEM coagulationtest with a platelet aggregometry test within one cartridge. Using sucha cartridge the preparation of a measurement which provides almostoverall information about the coagulation status of a patient merelyrequires the two steps of attaching the cartridge device 50 to themeasuring system 40 with the external control apparatus and injectingthe blood sample as one sample liquid 1. Considering the significance ofmore complex and time consuming preparation of severalthromboelastography or thromboelastometry tests, it is evident that theinvention is of great advantage for easier, safer and more accuratePOC-tests.

It is important to note that the cartridge devices 50 of the describedembodiments are suitable for different diagnostic tests likethromboelastometry, thromboelastography, platelet aggregometry andothers. Depending on which type of test or tests the cartridge device 50is designed for, there are different additional parts required whichinteract with the sample during measurement and/or an external controlapparatus. Possible adaptations for thromboelastometry and plateletaggregometry are described below.

FIG. 7a is a schematic drawing of a first embodiment of a probe element22 arranged in the measurement cavity 20 (see also FIGS. 10b and 13c ).FIGS. 7b and 7c show a second embodiment of the cartridge device 50 inform of a cartridge body 30 which comprises only the measurement cavity20. In the shown example this cavity 20 is accessible via a ductwork 15,15′ through a cavity wall. Alternatively the cavity 20 can be filledthrough a cover 31, e.g. by injection needles or the like.

The probe element 22 comprises the probe pin 3 (see FIG. 1) which isconnected to a flange 24 and a fixing section 25 via an intermediatesection 23. The probe element 22 is formed as a rotational part andfurther comprises a connector section 26 formed as a bore extendingwithin the probe element 22 along its longitudinal axis, which is therotational axis 5 as well (see FIG. 3).

The probe element 22 is arranged in the measurement cavity 20 of thecartridge body 30 of the cartridge device 50 as shown in FIG. 7b . Themeasurement cavity 20 is covered by the cover 31 (see also FIGS. 10b and13c ). The cover 31 comprises an opening with fixing means 32 above themeasurement cavity 20. The probe element 22 is arranged such that itsfixing section 25 corresponding to the fixing means 32 engage with them.In this manner the probe element 22 is detachably fixed to the cover 31.The fixing means 32 in this example are equipped with a circular nosecorresponding to a circular notch of the fixing section 25 of the probeelement 22. Other fixing means e.g. clip means or the like are possible.The flange 24 is in contact to the inner side of the cover 31.

During attaching the cartridge device 50 to the measuring system 40 (seealso FIG. 13c ) the shaft 6 of the measuring system 40 (see FIG. 3 andFIGS. 13a . . . c) is inserted with its bottom portion, an insertsection 6 a, into the connector section 26. By insertion into theconnector section 26 of the probe element 22 the probe element 22 willbe detached from the cover 31 not before the insert section 6 a iscompletely inserted in the connector section 26. Then the probe element22 will be put into in a measuring position as shown in FIG. 7c and keptthere. The insert section 6 a of the shaft 6 is engaged with theconnector section 26 of the probe element 22 e.g. by friction, clipmeans, thread or the like. In case of a thread the probe element 22 willbe hold by the engagement with or perforation of the cover 31. The shaft6 having a corresponding thread on its insert section 6 a will beinserted into the connector section of the probe element 22 by rotationuntil the insert section 6 a will be completely inserted into theconnector section 26. Then the shaft 6 can be pushed down and/or rotatedtogether with the fully engaged probe element 22 until the probe element22 will be detached from the cover 31. FIG. 7c shows the sample liquid1, which has been pumped into the measurement cavity 20. The probe pin 3of the probe element 22 is immersed in the sample liquid 1. Ameasurement as described above can be carried out. After the measurementthe cartridge device 50 is detached from the measuring system 40,wherein the shaft 6 is drawn up together with the probe element 22against the cover 31. The insert section 6 a of the shaft 6 will bedrawn out of the connector section 26 of the probe element 22 the flange24 thereof contacting and sealing the opening of the cover 31. Insteadof a flange 24 the upper end of the probe element 22 can have a largerdiameter than the opening in the cover 31. It is preferred that theinsert section 6 a of the shaft 6 and the measurement cavity 20, 20′ areformed symmetrically.

It is also possible to insert the insert section 6 a of the shaft 6 intothe connector section 26 of the probe element 22 and push the probeelement 22 down until its bottom contacts the bottom of the measurementcavity 20, 20′ ensuring that the insert section 6 a is completelyinserted into the connector section 26. Then the shaft 6 will be movedup into the measuring resp. working position of the probe element 22 asshown in FIG. 7 c.

FIGS. 8a . . . c are technical drawings of a preferred embodiment of theprobe element 22 of FIG. 7a . FIG. 8a shows a side view and FIG. 8bshows a top view of the probe element 22 parts of which have beendescribed above regarding FIG. 7a . Finally, FIG. 8c illustrates asectional view along rotational axis 5. The connector section 26 extendsover more than about 75% of the length of the probe element 22.

Now a third embodiment of the cartridge device 50 will be described withreference to FIGS. 9a , . . . d and FIGS. 10a . . . b.

FIG. 9a is a side view of a second embodiment of a third embodiment ofthe cartridge device 50 according to the invention. FIG. 9b is asectional view B-B of the cartridge device 50 of FIG. 9a . FIG. 9c is asectional view C-C of the cartridge device of FIG. 9a . FIG. 9b is asectional view D-D of the cartridge device of FIG. 9a . FIG. 10a is atop view of the cartridge device of FIG. 9a . FIG. 10b is a sectionalview E-E of the cartridge device of FIG. 10 a.

The cartridge device 50 of this example is equipped with the ductwork 13and 15. The ducts are formed with an diameter of approximately 1 mm inthis embodiment. The ductwork requires that the cartridge device 50comprises two parts: the cartridge body 30 and the cover 31, which areglued or welded together to obtain a leak-proof device. The cartridgebody 30 is relative rigid and the cover 31 is formed as an elastic part.So it is possible to integrate the pump means 18 into the cover 31.Moreover, the cover 31 covers the receiving cavity 16 with the receivingcavity cover 33 a and forms a type of liner wall 33 and a separationwall 34 forming an inlet for the inlet duct 13 within the receivingcavity 16. The receiving cavity cover 33 a might act as a self seal forinjection of a sample liquid 1 by a syringe for example. The cover 31forms top parts of the ductwork 13 an 15 and a cover of the measurementcavity 20 (see also FIGS. 7b . . . c). In this example the pump means 18comprises a pump membrane 35 formed by the cover 31. The pump membrane35 cooperates with a pump cavity 36 formed with a pump cavity bottom 36a in the cartridge body 30 below the pump membrane 35.

In this embodiment a reagent cavity 19, 19′ is formed, e.g. by sectionsof the ductwork or/and the pump means 18, 18′ in which the reagents canbe stored resp. deposited, especially on the pump cavity bottom 36 a,for example.

The pump means 18 will now be described with reference to FIGS. 11a . .. b and FIG. 12.

FIG. 11a is a sectional view of the pump means 18, 18′ of the cartridgedevice 50, FIG. 11b is a sectional view of the pump means 18 of FIG. 11aIn operated position, and FIG. 12 is a schematic top view of the pumpmeans 18 of FIG. 11 a.

In this example the pump cavity 36 is connected to the inlet duct 13 viaan inlet valve 37 and to the outlet valve via an outlet valve 38.Actuation of the pump membrane 35 (shown in FIG. 11b in a working cycle)by an appropriate actuating means (not shown) of the control apparatusthe pump means 18 will create a directed flow of the sample liquid 1 ina flow direction 39 depicted by the arrows. The pump membrane 35 beingan integrated part of the cover 31 can be made of the cover material ora part made of another material integrally manufactured with the cover31, e.g. two components manufacturing. The valves 37, 36 can be a typeof non-return valve. FIG. 12 shows a top view of the pump means in aschematic way.

An external force exerted on the pump membrane 35 increase the pressurewithin the pump cavity 36 and opens outlet valve 38 and closes inletvalve 37. Releasing the external force the elastic pump membrane 35returns into the position shown in FIG. 11a whereby outlet valve 38 willbe closed and inlet valve 37 opened to let sample liquid 1 into the pumpcavity 36. This mechanism is state of the art according to DE10135569.In context with the present invention the actuation means of the controlapparatus activating the pump membrane 35 from outside has the advantageof strict separation between those parts coming into contact with thesample liquid 1 and the control apparatus. At the same time the totalnumber of parts required for the cartridge device 50 being a disposablepart as well is kept on a minimum.

Now the measuring system 40 according to the invention is described inan embodiment with reference to FIGS. 13a . . . c.

FIG. 13a , is a side view of an embodiment of the measuring system 40,FIG. 13b is a top view of the measuring system 40 of FIG. 13a , and FIG.13c is a sectional view H-H of the measuring system 40 of FIG. 13 b.

The measuring system 40 comprises an interface element 41 to which thecartridge device 50 is attached and fixed. The interface element 41 isshown in FIGS. 13a to 13c in way of example as a base plate. Thefunction of the interface element 41 is to support the shaft 6 and tomaintain its position and thus the position of the probe element 22fixed to the insert section 6 a in a measurement position. The interfaceelement 41 can be connected to the whole cover 31 as shown in FIGS. 13ato 13c or only to parts of the cover 31, e.g. surrounding the rotationaxis 5. The shaft 6 is rotatable supported in a bearing 7 within a shaftpassage 44 (FIG. 13c ) and can be rotated around the rotation axis 5(see also FIG. 3) by driving the spring 9 via driving means (not shown).The detecting means 10 cooperate with the mirror 8 fixed on the shaft 3,also shown in FIG. 3. The control apparatus mentioned above is not shownas well, but easy to imagine. Its actuation and/or operating means canaccess the pump means 18 through an opening pump access 42 in theinterface element 41. The receiving cavity 16 is accessible throughanother inlet opening 43. These and other different passages or passageways of the interface element 41 to have access to the cartridge device50 and/or its cover 31 are illustrated by FIG. 13b as a top view of themeasuring system 40 of FIG. 13a . Passage holes 44 a are arranged nextto the rotational axis 5 to form an access to the cover 31 above themeasurement cavity 20, 20′, e.g. for injection of liquid sample orreagents. Additional access passage holes can be arranged in theinterface element 41, e.g. above the ductwork to access said ductwork.

FIG. 13c illustrates a sectional view H-H of FIG. 13b showing themounted cartridge device 50 and the measuring system 40. The shaft 6with its insert section 6 a is inserted into the probe element 22 andkeeps it in a measurement position as mentioned above. This embodimentcomprises only one measurement cavity 20, but it is apparent to a personskilled in the art that modifications and combinations of the inventioncan be carried out in different ways.

Thus it is possible to e.g. arrange a reagent receptacle 19 b in ablister receptacle e.g. as shown in FIG. 14 which is a sectional view ofthe reagent receptacle 19 b of a third embodiment of the cartridgedevice 50 according to the invention. The receptacle 19 b containsreagent 21 hold within a chamber defined by a blister cover 49, a bottompart 48 and a frame 47 hold in a retaining ring 46 within an reagentcover opening 45 in the cover 31 above the reagent cavity 19, 19′ with areagent cavity bottom 19 a, 19 a′. Upon exertion of a force by thecontrol apparatus onto the blister cover 49 the bottom part 48 will openand discharge the reagent 21 into the reagent cavity 19, 19′. Thereceptacle 19 b can be fixed to the cover by e.g. clip means asdepicted. The frame 47 can be a reinforced ring. The blister cover 49 isreinforced so that it will not break when a force is exerted on it. Thusthe leak-tightness of the cartridge device 50 will be ensured. In thisway a unitized construction system can be made, wherein the respectivereagents can be easily integrated into the cartridge device 50. It isalso advantageous that the reagents can be designed as a small componentbeing cooled resp. transported and supplied easily.

It is also possible to insert reagent receptacles into provided cavitiesbeing connected to the ductwork. The reagents can be designed asglobules with an appropriate diameter so that they cannot flow throughopenings into the ductwork before being dissolved by the sample liquid.

FIG. 15 is a schematic drawing of a second embodiment of a probe element22′. The probe element 22′ is arranged in the measurement cavity 20. Theprobe pin 3 is provided with a dimple 29 at its bottom side. The dimple29 forms with a nose 29 a a toe bearing to support the probe element22′. The probe element 22′ is similar to the probe element 22 of FIG. 7a, but has no fixing section 25, only the flange 24. The connectorsection 26 comprises a top end formed with an insertion guide 27 for theinsertion section 6 a of the shaft. The probe element 22′ is hold in themeasurement cavity 20 in a specific manner so that the insertion section6 a of the shaft 6 can be inserted easily through an opening 32 a of thecover 31 which has no fixing means. The insertion section 6 a can engagewith a groove 28 inside the connector section 26 of the probe element22′. After that engagement which is supported by the toe bearing theshaft 6 will be drawn up together with the probe element 22′ in themeasuring position. It is a matter of fact that other engagement meanscan be used.

LIST OF REFERENCE NUMERALS

-   1 Sample liquid-   2 Cup-   3 Probe pin-   4 Torsion wire-   5 Rotation axis-   6 Shaft-   6 a Insert section-   7 Bearing-   8 Mirror-   9 Spring-   10 Detecting means-   11 Base plate-   12 Cup holder-   13, 13′ Inlet duct-   14, 14 Intermediate duct-   15, 15′ Outlet duct-   16, 16′ Receiving cavity-   17 Branch duct-   18, 18′ Pump means-   19,19′ Reagent cavity-   19 a, 19′a Regent cavity bottom-   19 b Reagent receptacle-   20, 20′ Measurement cavity-   21, 21′ Reagent-   22, 22′ Probe element-   23 Intermediate section-   24 Flange-   25 Fixing section-   26 Connector section-   27 Insertion guide-   28 Groove-   29 Dimple-   29 a Nose-   30 Cartridge body-   31 Cover-   32 Fixing means-   32 a Opening-   33 Wall-   33 a Receiving cavity cover-   34 Separation wall-   35 Pump membrane-   36 Pump cavity-   36 a Pump cavity bottom-   37 Inlet valve-   38 Outlet valve-   39 Flow direction-   40 Measuring system-   41 Interface element-   42 Pump access-   43 inlet opening-   44 Shaft passage-   44 a Passage hole-   45 Reagent cover opening-   46 Retaining ring-   47 Frame-   48 Bottom foil-   49 Blister cover-   50 Cartridge device

1. A cartridge for a measuring system configured to measure aviscoelastic characteristic associated with a liquid, the cartridgecomprising: one or more testing cavities, a testing cavity beingassociated with an element for performing a test to determine theviscoelastic characteristic associated with a liquid; one or morereceiving cavities, a receiving cavity for receiving a component of theliquid; one or more reagent cavities, a reagent cavity for holding atleast one reagent; and ductwork connecting the receiving cavity, thereagent cavity, and the testing cavity; wherein the reagent cavity isconfigured to receive the component of the liquid from the receivingcavity and to allow at least part of the liquid, which comprises amixture of the component and the at least one reagent, to transfer intothe ductwork; wherein the ductwork comprises a first duct connecting thereceiving cavity to the reagent cavity and a second duct connecting thereagent cavity to the testing cavity so as to create a flow path fromthe receiving cavity to and through the reagent cavity and subsequentlyto the testing cavity; and wherein the ductwork is configured so that,in response to negative pressure at the first duct, the component andthe at least one reagent mix to form the liquid during transport throughthe ductwork.
 2. The cartridge of claim 1, wherein the component of theliquid comprises a blood sample.
 3. The cartridge of claim 1, whereinthe ductwork is configured for connection to at least one pump forcontrolling transporting at least part of the component from thereceiving cavity to the reagent cavity via the ductwork.
 4. Thecartridge of claim 1, wherein the one or more receiving cavitiescomprise a second receiving cavity, wherein the one or more testingcavities comprise a second testing cavity, and wherein the one or morereagent cavities comprise a second reagent cavity, and wherein theductwork comprises a third duct connecting the second receiving cavityto the second reagent cavity and a fourth duct connecting the secondreagent cavity to the second testing cavity so as to create a secondflow path from the second receiving cavity through the second reagentcavity to the second testing cavity.
 5. The cartridge of claim 4,wherein different reagents are positioned in each of the reagent cavityand the second reagent cavity.
 6. The cartridge of claim 1, wherein thereagent cavity comprises a place along the flow path where the at leastone reagent is deposited.
 7. The cartridge of claim 1, wherein thereagent cavity comprises a cavity along the flow path that is largerthan the fluid flow path and where the at least one reagent isdeposited.
 8. The cartridge of claim 1, wherein the ductwork isconfigured for connection to one or more pumps to implement pressurechanges to control flow of fluids between the receiving cavity and thetesting cavity.
 9. The cartridge of claim 1, wherein the elementcomprises a probe.
 10. The cartridge of claim 1, wherein at least partof the probe is exterior to the testing cavity.
 11. A system configuredto measure viscoelastic characteristics associated with a blood sample,the system comprising: a cartridge comprising: a first receiving cavityfor receiving a first part of the blood sample, a second receivingcavity for receiving a second part of the blood sample, the secondreceiving cavity being separate from the first receiving cavity, a firstreagent cavity for holding at least one reagent, a second reagent cavityfor holding at least one reagent, a first testing cavity, a secondtesting cavity, and ductwork comprising: a first duct connected to thefirst reagent cavity for fluid communication with the first receivingcavity, a second duct connected to the first reagent cavity for fluidcommunication with the first testing cavity, a third duct connected tothe second reagent cavity for fluid communication with the secondreceiving cavity, and a fourth duct connected to the second reagentcavity for fluid communication with the second testing cavity; a firstreagent that is in the first reagent cavity for mixing with the firstpart of the blood sample in the first reagent cavity to produce a firstliquid to for transport in the second duct; a second reagent that isdifferent than the first reagent and that is in the second reagentcavity for mixing with the second part of the blood sample in the secondreagent cavity to produce a second liquid for transport in the fourthduct; a first element arranged relative to the first testing cavity formeasuring a viscoelastic characteristic based on the first liquid; and asecond element arranged relative to the second testing cavity formeasuring a viscoelastic characteristic based on the second liquid. 12.The system of claim 11, wherein the first and second reagents comprisereagent globules configured to dissolve in respective parts of the bloodsample.
 13. The system of claim 11, where the first reagent comprisesone of: a first combination of reagents that interact with the firstpart of the blood sample and that are configured to activate coagulationvia an intrinsic pathway; a second combination of reagents that interactwith the first part of the blood sample and comprise (i) a reagent or acombination of reagents configured to activate coagulation and (ii) areagent or a combination of reagents configured to suppress thrombocytecontraction; or a third combination of reagents that interact with thefirst part of the blood sample and that are configured to activatecoagulation via an extrinsic pathway.
 14. The system of claim 11,wherein the second reagent is different from the first reagent.
 15. Thesystem of claim 11, further comprising: a first pressure-controlled stopto inhibit entry of the first part of the blood sample into the firstreagent cavity; and a second pressure-controlled stop to inhibit entryof the second part of the blood sample into the second reagent cavity.16. The system of claim 11, wherein the first pressure-controlled stopcomprises a first valve and the second-pressure controlled stop comprisea second valve.
 17. The system of claim 11, wherein at least part of thefirst element is external to the first testing cavity; and wherein atleast part of the second element is external to the second testingcavity.
 18. The system of claim 11, wherein then first receiving cavity,the first reagent cavity, the first testing cavity, the first duct, andthe second duct define a first fluid flow path, the first reagent cavitycomprising a first place along the first flow path where the firstreagent is deposited; and wherein then second receiving cavity, thesecond reagent cavity, the second testing cavity, the third duct, andthe fourth duct define a second fluid flow path, the second reagentcavity comprising a second place along the second flow path where thesecond reagent is deposited.
 19. The system of claim 11, wherein thenfirst receiving cavity, the first reagent cavity, the first testingcavity, the first duct, and the second duct define a first fluid flowpath, the first reagent cavity comprising a first deep cavity along thefirst flow path where the first reagent is deposited, the first deepcavity comprising a cavity that is larger than the first flow path; andwherein then second receiving cavity, the second reagent cavity, thesecond testing cavity, the third duct, and the fourth duct define asecond fluid flow path, the second reagent cavity comprising a seconddeep cavity along the second flow path where the second reagent isdeposited, the second deep cavity comprising a cavity that is largerthan the second flow path.
 20. A system comprising: means fortransporting blood or a liquid based on the blood between a receivingcavity and a testing cavity, the means for transporting comprising afluid flow path; means for producing the liquid based on the blood bycombining the blood with one or more reagents along the fluid flow pathand prior to the liquid reaching the testing cavity; apressure-controlled stop configured to react to pressure to inhibit flowof the blood from the receiving cavity toward the means for producing;and a probe for determining a viscoelastic characteristic based on theliquid in the testing cavity.
 21. The system of claim 20 wherein thepressure-controlled stop comprises a valve.
 22. The system of claim 20,wherein at least part of the probe is external to the testing cavity.23. The system of claim 20, further comprising: a pump to provide atleast one of negative or positive pressure to the means for transportingto control fluid flow of the blood or the liquid based on the blood. 24.A cartridge for a measuring system, the cartridge comprising: testingcavities comprising at least (i) a first testing cavity for holding afirst liquid that is based on a mixture of first blood and at least onefirst reagent and (ii) a second testing cavity for holding a secondliquid that is based on a mixture of second blood and at least onesecond reagent; flow paths comprising at least (i) a first flow path fortransporting the first liquid to the first testing cavity, the firstflow path comprising first ductwork that at least partly enables mixingof the first blood and the at least one first reagent to produce thefirst liquid, and (ii) a second flow path for transporting the secondliquid to the second testing cavity, the second flow path comprisingsecond ductwork that at least partly enables mixing of the second bloodand the at least one second reagent to produce the second liquid; andone or more valves that are controllable to cause mixing of the firstblood and the at least one first reagent and mixing of the second bloodand the at least one second reagent.
 25. The cartridge of claim 24,wherein the at least one of the first reagent comprises one of thefollowing, and the at least one second reagent comprises a different oneof the following than the at least one first reagent: a firstcombination of reagents that interact with the first blood or the secondblood and that are configured to activate coagulation via an intrinsicpathway; a second combination of reagents that interact with the firstblood or the second blood and comprise (i) a reagent or a combination ofreagents configured to activate coagulation and (ii) a reagent or acombination of reagents configured to suppress thrombocyte contraction;or a third combination of reagents that interact with the first blood orthe second blood and that are configured to activate coagulation via anextrinsic pathway.
 26. The cartridge of claim 25, wherein the first flowpath comprises a first reagent cavity, the first reagent cavitycomprising a first place along the first flow path where the at leastone first reagent is deposited; and wherein the second flow pathcomprises a second reagent cavity, the second reagent cavity comprisinga second place along the second flow path where the at least one secondreagent is deposited.
 27. The cartridge of claim 25, wherein the firstflow path comprises a first reagent cavity, the first reagent cavitycomprising a first deep cavity along the first flow path where the atleast one first reagent is deposited, the first deep cavity comprising acavity that is larger than the first flow path; and wherein the secondflow path comprises a second reagent cavity, the second reagent cavitycomprising a second deep cavity along the second flow path where the atleast one second reagent is deposited, the second deep cavity comprisinga cavity that is larger than the second flow path.
 28. The cartridge ofclaim 25, wherein the flow paths are configured for connection to one ormore pumps to implement pressure changes to control flow of fluids alongthe first flow path and the second flow path using positive and negativepressure.
 29. The cartridge of claim 25, wherein the testing cavitiesare associated with probes to measure viscoelastic characteristics basedon the first liquid and the second liquid, the probes being associatedwith detectors for detecting the viscoelastic characteristics.
 30. Thecartridge of claim 25, wherein the first flow path is configured toreceive the first blood from a bottom of an additional cavity holdingthe first blood.